Although there have been significant advances in the molecular biology, biochemistry, and biotechnology of important cellular processes, they have not been translated into high cure rates for most cancers. The current surgical, chemo-, and radiotherapeutic techniques are generally inadequate and result in enormous patient distress with poor prognoses. We have proposed to utilize combinatorial phage-display peptide libraries as a foundation for a cancer therapy. We have developed a new library approach based on pVII-plX display that is more powerful than standard peptide libraries. With this display format, not only is there combinatorial diversity with respect to sequence space, but also with respect to interactions in conformational space. Our preliminary results demonstrated the ability to construct a 15-mer random peptide library and to rapidly select peptides that targeted and penetrated cancer cells. Cancer cell lines were shown to internalize a selected peptide with high specificity versus other cell types. We propose to further refine the selection protocols to enable complete specificity of a targeted carcinoma as opposed to normal cells. In addition, appropriate peptides were prepared in phage-free and synthetic forms and the active species was shown to be a dimer. We plan biophysical analyses and structure-activity studies for selected peptides. We have also proposed to elucidate the kinetics and mechanism of action of cell penetration and to identify a putative membrane receptor. Finally, specific, cell-penetrating peptides will be conjugated with anticancer drugs and tested in vitro for cancer cell killing, and in vivo for activity against tumors and metastasis in a mouse model. These studies will serve as a foundation for potential new chemotherapeutic agents. The refinement of cell-penetrating peptide technology will allow the delivery of cytotoxic compounds specifically to the interior of tumor cells which would virtually eliminate systemic toxicity and result in the efficient eradication of cancer. [unreadable] [unreadable]